B cells have important antibody-independent effector functions including cytokine production that parallels T cells in magnitude and regulation. It has also been established that B cell-mediated antibody-independent effector functions are central to the pathogenesis of autoimmune diseases. These observations highlight the need to understand the precise phenotype and function of human effector B cells and their disregulation in autoimmunity. However, both in mice and humans, effector B cells are ill-defined and poorly understood. Over the last 3 years, we have identified a previously unrecognized population of human B cells that while displaying isotype switch and bearing a significant degree of somatic hypermutation, are distinct from conventional memory cells in the lack of CD27 expression; lower degree of mutation; expression of activation markers; expression of markers of trafficking to systemic inflamed tissues; and dependence on BAFF for survival. All the evidence combined, we postulate that these cells represent effector B cells that are greatly expanded systemically in SLE and in the synovial fluid of patients with Rheumatoid Arthritis and contribute to the pathogenesis of these diseases in antibody-independent fashion. The overall goal of this project is to understand the ontology, homeostasis, selection and function of effector B cells in human autoimmune disease with particular emphasis in SLE. This goal will be accomplished through the following specific aims: 1) To define the ontology of effector B cells (Beff) in SLE; 2) To understand the homeostasis of effector B cells in SLE; 3) To understand the selection of autoreactivity within the Beff effector compartment; and 4) To understand division of labor in human effector B cells. The information obtained should substantially improve our ability to therapeutically target populations of interest either for enhancement (vaccine responses) or dampening (autoimmune responses and transplantation). Finally, the knowledge gained will also greatly facilitate investigators ability to understand the immunological mechanisms behind the benefit (or lack thereof) of clinical interventions such as vaccination or B cell targeting therapies. This project has great synergy with the studies of other unique regulatory and effector B cell populations studied in projects 1 (human transitional cells) and projects 3-4 (mouse effector and Bin cells).